Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors. It is often difficult to find an adenoma in patients with Cushing's disease (CD) whose preoperative magnetic resonance imaging (MRI) is normal. Better localizing modalities are needed. We evaluated the utility of inferior petrosal sinus sampling (IPSS) to predict adenoma location. Potential false-negative results, the most common type of diagnostic error with IPSS for the differential diagnosis of CS, can be identified by peak IPSS ACTH values < 400 pg/ml. When MRI is normal, IPSS can be used to guide surgical exploration in patients with negative preoperative imaging. However, because of the limited accuracy of lateralization, thorough exploration of the pituitary gland is required when an adenoma is not readily discovered based on predicted location. The glucocorticoid antagonist mifepristone blocks cortisol action and thus might be an effective treatment of Cushing's syndrome. This hypothesis is being tested in an ongoing clinical trial of patients with presumed ectopic ACTH secretion. We have also observed that two individuals with a negative octreoscan initially converted that to a positive scan after mifepristone treatment.